The renin angiotensin system blockade in kidney transplantation: pros and cons.

Besides the immunological mediated damage on the graft, the intrarenal renin-angiotensin system (RAS) is viewed as an additional mechanism in the development and progression of chronic allograft injury. RAS blocking agents efficiently control post-transplant hypertension and are useful to reduce proteinuria and for treating post-transplant erythrocytosis. However, RAS blockade is associated with some potentially relevant adverse events as hyperkalemia, anemia, and even to a decline in renal function. There are consistent experimental data showing that RAS blockade has a therapeutic effect on chronic allograft injury. Some clinical studies have shown that RAS blockade reduces transforming growth factor-beta1 and other markers of fibrosis but, up to now, there is not convincing evidence supporting that RAS blockade has further benefit on the progression of chronic allograft injury in comparison with other antihypertensive interventions. Theoretically, RAS blockade may also improve cardiovascular disease, which constitutes the main cause of mortality and morbidity in renal allograft recipients. Nevertheless, to date there is lack of evidence for supporting that RAS blockade improves neither graft nor patient survival in comparison with other antihypertensive drugs. Randomized, prospective, double blind, placebo-controlled trials with enough sample size and follow-up are needed to address the potential role of RAS blockade to improve graft and patient outcome. Meanwhile, we should empirically balance case to case the pros and cons of RAS blockade in renal transplantation.     

Role of vasopressinergic V1 receptor agonists in the treatment of perioperative catecholamine-refractory arterial hypotension

Three pathways are critically involved in blood pressure regulation during anaesthesia, i.e. the sympathetic nervous system, the renin angiotensin system (RAS), and the vasopressinergic system. The fact that anaesthetic agents typically blunt the regulatory role of the adrenergic system emphasises the importance of the remaining compensatory mechanisms. In patients chronically treated with RAS antagonists, such as angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists, however, this mechanism is also blunted, possibly resulting in absolute dependency of blood pressure regulation on the vasopressinergic system. To date, several small-scale clinical trials demonstrated the efficacy of V1 receptor agonists in reversing perioperative catecholamine-refractory hypotension in patients with chronic RAS blockade. Therefore, perioperative administration of a V1 agonist, such as terlipressin, may be a rational approach to treat severe hypotension non-responsive to conventional treatment strategies. In the absence of catecholamine resistance and RAS blockade, administration of V1 agonists may contribute to a dose-dependent reduction in regional splanchnic vasoconstriction. Likewise, bolus infusion may result in coronary vasospasm and is thus not recommended for routine clinical use. Future large-scale randomized, controlled clinical trials are warranted to evaluate the role of V1 agonists in the treatment of perioperative hypotension in more detail.     

环孢素A对大鼠慢性肾毒性模型肾素-血管紧张素系统的影响

目的　探讨环孢素A (CsA)慢性肾毒性的发生机理。方法　采用放射免疫分析的方法 ,观察进低盐饮食的大鼠在灌服CsA 30mg·kg- 1 ·d- 1 2 8d后血浆肾素活性 (PRA)、血管紧张素Ⅱ(AngⅡ )、醛固酮水平的变化 ,以及复方丹参注射液、贝那普利对上述改变的防护作用。结果　CsA可引起大鼠血浆PRA、AngⅡ水平明显升高 ;丹参对这些改变影响不明显 ,而贝那普利对大鼠PRA、AngⅡ水平的升高有明显的抑制作用。血浆醛固酮水平 ,各组比较 ,只有给予贝那普利者明显下降 ,其余各组之间血浆醛固酮水平的差异无显著性 (P >0 .0 5)。结论　CsA的慢性肾毒性损伤可能与肾素 血管紧张素系统 (RAS)的激活 ,尤其是与AngⅡ的增加有关 ;CsA不引起血浆醛固酮水平的升高     

Association between peri‐operative angiotensin‐converting enzyme inhibitors and angiotensin‐2 receptor blockers and acute kidney injury in major elective non‐cardiac surgery: a multicentre,prospective cohort study

The peri‐operative use of angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri‐operative period. This study aimed to investigate if withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers peri‐operatively reduces the risk of acute kidney injury following major non‐cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi‐level models were used to account for centre‐level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers withheld during the peri‐operative period. One hundred and seventy‐five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58–1.34); p = 0.567).     

Angiotensin converting enzyme inhibitors maintain polytetrafluroethylene graft patency.

BACKGROUND: A patent vascular access is crucial for hemodialysis patients. Stenosis and thrombosis lead to access failure. Endothelial injury via angiotensin II may mediate a hyperplastic and prothrombotic response. Thus angiotensin II inhibition with angiotensin-converting enzyme inhibitors (ACEI) may prolong vascular access patency. This study determines the impact of ACEI use on access patency in both polytetrafluroethylene (PTFE) grafts and fistulas. METHODS: Demographics, access history and medication use were reviewed in 266 accesses from four dialysis centres. Primary patency, date of surgery to date of first access failure, was determined. Excluded accesses had incomplete history or <30 day patency. Groups divided into ACEI and non-ACEI based on patient use of ACEI during access patency. Statistical methods included: unpaired Student t to compare continuous variables, Chi-square and Fisher's Exact test to compare proportions and evaluate for risk estimation, univariate and multivariate Cox regression to investigate variables associated with duration of access patency. Cox-adjusted survival and Hazard curves were obtained for significant variables. RESULTS: Non-ACEI (PTFE) graft group included more males and older patients; however, when these covariates were adjusted during both univariate and multivariate regression, suggested, only ACEI use was associated with greater access patency duration, 671.7 days (ACEI) vs 460.0 days (non-ACEI), p=0.012. ACEI group had fewer clotting events, 55% versus 71% (non-ACEI) group, p=0.042. ACEI use had little effect on primary patency of the fistula however male gender increased time to fistula failure, p=0.002. CONCLUSIONS: Retrospective evaluation suggests ACEI use in patients with PTFE grafts may prolong and maintain patency. Fistula patency is affected by gender with longer patency noted in males. Further prospective studies are necessary to confirm the role of ACEI in maintaining vascular access patency.     

Intravenous enalaprilat and autonomic reflexes

Thirty healthy patients, who were to undergo surgery which required tracheal intubation, were given an intravenous injection of enalaprilat (either 0.5 mg, 1 mg, 2 mg or 4 mg; six patients for each dose) or normal saline 17 minutes before induction of anaesthesia with thiopentone 3-5 mg/kg, and suxamethonium 1.5 mg/kg. Postural manoeuvres were performed 5 minutes before and 6, 11 and 16 minutes after enalaprilat or saline. Complete inhibition of angiotensin converting enzyme occurred with all doses of enalaprilat, which allowed the four different treatment groups to be considered as one large treated group. The mean arterial pressure was almost unchanged during the postural manoeuvres; the heart rate increased, mostly similarly (by approximately 10%) in both groups. Mean arterial pressure in the recumbent position decreased over the 17 minutes before induction in the enalaprilat group, and increased slightly in the control group (treated mean, -5.0%; controls mean, 1.8%; difference, -6.8%; 95% confidence intervals of difference, -2.3 to -11.3%, p less than 0.01). This difference was again seen after induction (treated, -8.0%; controls, 7.7%; confidence intervals of difference, -0.6 to -31%) and for a 5-minute period shortly after tracheal intubation. The increases in mean arterial pressure produced by intubation itself were similar in both groups (treated, + 36%; controls, + 35%; 95% confidence intervals of difference, -16% to + 18%). Changes in heart rate after induction were also similar in both groups. It is concluded that intravenous enalaprilat acted as a hypotensive agent with a sparing effect on autonomic reflexes, both before and after induction of anaesthesia.     

Angiotensin converting enzyme inhibitor use soon after renal transplantation: a randomized, double-blinded placebo-controlled safety study

Activation of the renin-angiotensin system (RAS) followed by increased inflammatory cytokines may be important in the pathogenesis of chronic allograft dysfunction. As many renal transplant recipients show chronic changes on biopsy within the first year, early RAS blockade with angiotensin converting enzyme inhibitor (ACEI) could be beneficial. However, it remains unclear that early ACEI use is safe. We conducted a prospective, randomized, placebo-controlled trial to assess the safety of enalapril 5 mg during the early post-transplant period. Subjects took the study medication for six months. Primary endpoints were serum potassium (K) >5.9 mEq/L and 30% increase in baseline creatinine. A total of 53 subjects were randomized, and of them, 27 received the study drug. Twenty-nine subjects, 14 ACEI and 15 controls, completed the six-month protocol without reaching an endpoint. Patients on ACEI had higher K and higher BUN at six months. Serum creatinine, hematocrit, and urinary protein were not different. There was no difference in urinary TGF-β1. Twenty-four subjects reached study endpoints. When the common clinical endpoints of elevated creatinine and hyperkalemia were combined, ACEI group had significantly increased endpoints vs. control (10/13, 77% vs. 5/11, 45%, p < 0.05). We conclude that ACEI use in the early post-transplant period can be safe but patients must be carefully selected and monitored for elevations in serum creatinine and potassium. Whether early ACEI is beneficial in preserving allograft function requires further study.     

贝那普利防护环孢素A慢性肾毒性的实验研究

目的 观察贝那普利对环孢素A（CsA)慢性肾毒性的防护作用。方法 将大鼠分为对照组、单纯级CsA组及给CsA和贝那普利组,观察给药后14d和28d各组大鼠24h 的尿量及N－乙酰－β－D-氨基葡萄糖苷酶（NAG）水平,计算内生肌酐清除率及滤过钠排泄分数（FENa）,并对肾组织进行组织学观察和免疫组织化学检测。结果 CsA能诱导肾小球滤过率下降,增加尿中NAG的排泄,导致肾间质纤维化和小动脉病变等;贝那普利能改善上述改变,减低肾内转化生长因子－β1（TGF－β1）的表达。结论 贝那普利对CsA的慢性肾毒性有明显的防护作用。     

Postoperative hypotension associated with enalapril

We describe the case of a patient treated for hypertension with the angiotensin converting enzyme inhibitor enalapril, who developed hypotension after recovery from anaesthesia.     

Prevention of stone formation and bone loss in absorptive hypercalciuria by combined dietary and pharmacological interventions

PURPOSE: We determined whether dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate treatment, would prevent stone formation and avert bone loss in 18 men and 10 women with type I absorptive hypercalciuria. MATERIALS AND METHODS: Patients were treated with thiazide (20) or indapamide (8) and potassium citrate (average dose 35 mEq. daily) for 1 to 11 years (mean 3.7) while maintained on low calcium oxalate diet. Serum and urinary chemistry studies and bone mineral density were measured at baseline and at the end of treatment. New stones formed were quantitated during 3 years before and during treatment. RESULTS: During treatment urinary calcium significantly decreased (346 +/- 85 to 248 +/- 79 mg. daily, p <0.001) but urinary oxalate did not change. Urinary pH and citrate significantly increased, and urinary saturation of calcium oxalate significantly decreased by 46%. Stone formation rate decreased significantly from 2.94 to 0.05 per year (p <0.001). L2-L4 bone mineral density increased significantly by 5.7% compared to normal peak value, and by 7.1% compared with normal age and gender matched value. Femoral neck bone mineral density also increased significantly. CONCLUSIONS: Dietary restriction of calcium and oxalate, combined with thiazide and potassium citrate, satisfactorily controlled hypercalciuria, prevented the secondary increase in urinary oxalate, reduced urinary saturation of calcium oxalate, virtually eliminated recurrent stone formation, and increased bone density of the spine and femoral neck. Thus, this dietary pharmacological program controlled stone formation as well as bone loss that often accompany type 1 absorptive hypercalciuria.     

Report of takotsubo cardiomyopathy occurring during cardiopulmonary bypass

On weaning from cardiopulmonary bypass, a 59-year-old Japanese woman with mitral valve plasty suddenly showed a greatly increased heart rate, and an electrocardiogram revealed elevated ST-segments. There was also abnormal wall motion in the inferior region and apical ballooning of the left ventricle. We diagnosed the condition as takotsubo cardiomyopathy (acute left ventricle apical ballooning syndrome), possibly caused by catecholamine release and regional stress-induced ischemia. We believe this to be the first case report of takotsubo cardiomyopathy observed during heart surgery. We hypothesize that the condition was mediated by regional myocardial stunning and that it could be prevented by administration of angiotensin converting enzyme inhibitors before surgery and by the use of superior biocompatible cardiopulmonary bypass components. Once takotsubo cardiomyopathy occurs, we recommend mechanical circulatory assistance during weaning from the bypass.     

Effect of combined angiotensin‐converting enzyme and aldosterone inhibition on plasma plasminogen activator inhibitor type 1 levels in chronic hypertensive patients

Aim: A possible link between the renin–angiotensin–aldosterone system (RAAS) and fibrinolysis has recently been suggested. Systemic infusion of angiotensin II results in an increase in plasminogen activator inhibitor type 1 (PAI‐1) levels and angiotensin‐converting enzyme inhibitors (ACEI) have been shown to decrease PAI‐1 levels. Moreover, recent data indicated that plasma aldosterone levels were positively correlated with plasma PAI‐1 levels. This study was designed to compare the effects of an ACEI with an ACEI in combination with an aldosterone antagonist on PAI‐1 levels in chronic hypertensive patients. Methods: Patients were randomized into two groups and were treated with either low salt diet plus fosinopril (group 1, n = 43) or low salt diet plus fosinopril plus spironolactone (group 2, n = 42). Plasma PAI‐1, tissue plasminogen activator (tPA) and plasma renin activity (PRA) levels were measured before and after 24 week treatment in both groups. Results: The mean basal PRA levels were similar in both groups. After antihypertensive therapy, the mean PRA increased significantly in both groups (P < 0.005). The mean plasma PAI‐1 levels were reduced in both treatment groups (P < 0.005). However, the reduction in group 2 was more pronounced (P < 0.05). Although after the treatment mean plasma levels of PAI‐1 significantly reduced in both groups, the reduction of PAI‐1 levels was more pronounced in group 2. Conclusion: Although the plasma levels of PAI‐1 significantly reduced after treatment in both groups, the reduction of PAI‐1 levels was more pronounced in group 2. These data indicated that administration of aldosterone antagonists in combination with ACEI had additional benefit on fibrinolysis in chronic hypertensive patients.     

Lithium carbonate in the preoperative preparation of Graves' disease

Lithium carbonate was given in the preoperative preparation of 12 patients with Graves' disease, the reasons for its use being side effects of thionamide in 9 patients, insufficient control by thionamide in 1 and psychic symptoms in 2. Lithium carbonate was often used in combination with other drugs, namely; thionamide in 4 patients, beta-adrenergic blockades in 5, reserpine in 5 and glucocorticoid in 1. This preoperative control significantly decreased the mean serum T₂ and T₄ levels from 656±55 ng/dl to 180±16 ng/dl and from 25.9±2.1 μg/dl to 9.7±1.5 μg/dl, respectively. The only adverse effect of lithium carbonate was pollakisuria observed in one patient. All patients underwent subtotal thyroidectomy uneventfully. It is concluded that the administration of lithium carbonate alone or in combination with other durgs is an effective method of preoperatively controlling hyperthyroidism when conventional antithyroid drugs show adverse effects.     

Angiotensin converting enzyme in renal ontogeny: hypothesis for multiple roles

Angiotensin converting enzyme (ACE) has multiple effects both as the enzyme which cleaves angiotensin II from angiotensin I and as that which breaks down bradykinin. The present study examines ACE mRNA and protein expression in the rat kidney during development. Changes in distribution and expression during development are consistent with suggestions that the renin angiotensin system is important in growth modulation, vascular development and regulation, and protein reabsorption.     

Purification and characterization of angiotensin converting enzyme-II from bovine seminal plasma

Angiotensin converting enzyme (EC 3.4.15.1) from bovine seminal plasma was shown to exist in two distinct forms. A lower molecular weight form of the enzyme having higher activity was purified to homogeneity. Final recovery of the enzyme was 18.37%. The apparent molecular weight of the enzyme was estimated to be 1.99 x 10(5) by gel filtration. A value of 1.8 x 10(5) was obtained for the reduced and denatured enzyme by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Stokes' radius, diffusion coefficient and intrinsic viscosity were determined to be 51.89 A degree, 4.2 x 10(-7) cm2/sec and 4.42 cc/g, respectively. Chloride ions were required for the enzyme activity. Studies with EDTA suggest that metal ions which are tightly bound, are required for its activity. Enzyme was inhibited by some heavy metal ions and required disulfide linkages at its active site. Trypsin treatment of the urea denatured enzyme produced a catalytically active Mr 32,000 daltons fragment.     

Cardiac Arrest during Total Hip Arthroplasty in a Patient on an Angiotensin Receptor Antagonist

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists (ARA) are effective and well-tolerated first-line drugs in the therapy of hypertension and, therefore, are frequently encountered in the perioperative setting. Hemodynamic compensation for volume depletion seen in the perioperative period is normally mediated by the renin–angiotensin system, which is blocked by ACEI/ARA. These drugs may contribute to severe hypotension during anesthesia induction and may have contributed to the cardiac arrest seen in this patient. Additional factors such as increased intra-abdominal pressures and respiratory obstructive episodes leading to diminished venous return, as well diuretic use and the fasting state, common in the perioperative orthopedic patient, are likely to have contributed as well. Medication use may be an easily modifiable risk factor for severe hypotension and possible cardiac arrest in the perioperative setting.     

Effect of angiotensin converting enzyme (ACE) and angiotensins on human sperm functions

Summary.  The presence of components of the renin angiotensin system (RAS) and specific receptors of angiotensin II in the female and male reproductive tract supports the hypothesis that reproductive functions may be controlled by RAS. Therefore, the present study investigated the influence of ACE and angiotensins on sperm functions and the sperm–egg interaction.
The experiments did not indicate direct effects of ACE on the capacitation process or acrosome reaction. Release of ACE from human spermatozoa during capacitation was not related to their ability to undergo acrosome reaction after stimulation with ionophore. Therefore, ACE release does not seem to be a useful clinical marker for human sperm capacitation. However, decreased binding of human spermatozoa to the oolemma of zona-free hamster oocytes after inhibition of ACE by captopril indicates that kininase II is involved in sperm–egg interactions. In contrast to other studies, incubation with captopril had no influence on sperm binding to the zona pellucida. Because effects of ACE on sperm–egg interactions but not on capacitation or acrosome reaction were observed, several experiments were performed to study the influence of substrates and products on the acrosome reaction. Angiotensin II induced the acrosome reaction dose-dependently, whereas angiotensin I had no effect on the acrosome reaction. The effect of angiotensin II on acrosome reaction seems to be calcium-dependent and mediated by protein kinases. Since a specific type 2 angiotensin II receptor inhibits the acrosome reaction induced by angiotensin II, this subtype of receptors may be present at the surface of sperm heads. Another clue for the presence of type 2 receptors on human spermatozoa is the finding that pertussis toxin did not inhibit the angiotensin II induced acrosome reaction. In contrast to type 1 angiotensin II receptors, type 2 receptors are known to be G-protein independent.     

不同种类降压药与骨质疏松症相关性研究进展

高血压和骨代谢在生理调节上有共同点，特定种类的降压药也可能影响骨密度或降低骨质疏松症相关骨折风险。虽然现有研究不足以明确哪类降压药对骨骼有益，但目前大部分研究支持血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂和?受体拮抗剂能够改善骨密度或降低骨折风险，袢利尿剂则增加骨折风险，而噻嗪类利尿剂和钙通道阻滞剂相关结论互相矛盾。基于高血压的高患病率及降压药的广泛使用，探讨不同种类降压药对骨骼的影响很重要。通过总结近年来关于不同种类降压药与骨质疏松症相关性研究，为易患骨质疏松症高危人群的高血压患者选择合适的降压药提供临床依据。     

不同阶段骨关节炎滑膜组织中肾素、血管紧张素转换酶及血管紧张素受体1、2的表达研究

目的研究不同阶段骨关节炎滑膜组织中的肾素(Renin)、血管紧张素转换酶(angiotensin converting enzyme,ACE)、血管紧张素受体1(angiotensin receptor 1,AT1R)和AT2R的表达差异。方法以2018年1月-12月因创伤行膝上截肢术、骨关节炎行人工全膝关节置换术的患者作为研究对象。共32例患者符合选择标准纳入研究,根据Kellgren-Lawrence(K-L)X线分级标准分为正常滑膜组(A组,9例)、中度骨关节炎滑膜组(B组,11例,K-L 3级)及晚期骨关节炎滑膜组(C组,12例,K-L 4级)。采用实时荧光定量PCR及Western blot检测各组滑膜组织中Renin、ACE、AT1R、AT2R mRNA及蛋白相对表达量。结果B、C组Renin、ACE、AT1R mRNA及蛋白相对表达量明显高于A组,C组ACE、AT1R mRNA及蛋白相对表达量以及Renin蛋白相对表达量明显高于B组;而B、C组AT2R mRNA及蛋白相对表达量明显低于A组,C组低于B组;上述指标组间比较差异均有统计学意义(P<0.05)。结论随骨关节炎严重程度增加,关节滑膜组织中Renin、ACE、AT1R表达明显高于正常人群,AT2R表达量呈下降趋势,提示上述指标与骨关节炎发展相关。